title: Central tolerance regulates B cells reactive with Goodpasture antigen alpha3(IV)NC1 collagen.
abstract: Patients and rodents with Goodpasture's syndrome (GPS) develop severe autoimmune crescentic glomerulonephritis, kidney failure, and lung hemorrhage due to binding of pathogenic autoantibodies to the NC1 domain of the alpha3 chain of type IV collagen. Target epitopes are cryptic, normally hidden from circulating Abs by protein-protein interactions and the highly tissue-restricted expression of the alpha3(IV) collagen chain. Based on this limited Ag exposure, it has been suggested that target epitopes are not available as B cell tolerogens. To determine how pathogenic anti-GPS autoantibody responses are regulated, we generated an Ig transgenic (Tg) mouse model that expresses an Ig that binds alpha3(IV)NC1 collagen epitopes recognized by serum IgG of patients with GPS. Phenotypic analysis reveals B cell depletion and L chain editing in Tg mice. To determine the default tolerance phenotype in the absence of receptor editing and endogenous lymphocyte populations, we crossed Tg mice two generations with mice deficient in Rag. Resulting Tg Rag-deficient mice have central B cell deletion. Thus, development of Tg anti-alpha3(IV)NC1 collagen B cells is halted in the bone marrow, at which point the cells are deleted unless rescued by a Rag enzyme-dependent process, such as editing. The central tolerance phenotype implies that tolerizing self-Ag is expressed in bone marrow.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Susan C
authors.initials: SC
authors.lastname: Su
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Hecox
authors.forename: Graham F
authors.initials: GF
authors.lastname: Brady
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Mackin
authors.forename: Amy G
authors.initials: AG
authors.lastname: Clark
authors.forename: Mary H
authors.initials: MH
authors.lastname: Foster
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001323:Autoantibodies / Q000096:biosynthesis / Q000502:physiology; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D018398:Homeodomain Proteins; C057112:type IV collagen alpha3 chain; C064658:RAG-1 protein